PROJECT SUMMARY/ABSTRACT One of the primary clinical challenges in prostate cancer is the management of screen-detected, localized disease. Recent years have seen a dramatic increase in ?active surveillance? (conservative management) of low-risk disease. A corollary has been increased attention to the algorithms used for risk stratification. Although Gleason grade is strongly predictive of oncologic outcome, it is clear that, while some men with low Gleason grade on biopsy do in fact harbor high-risk disease, many men with higher Gleason grade would not in fact experience symptoms of prostate cancer during the natural course of their life even if left untreated. We have shown that a statistical model based on a panel of kallikrein markers in blood ? total PSA, free PSA, intact PSA and human kallikrein 2 (hK2) ? strongly predicts risk of high-grade (Gleason score ?7) cancer on biopsy. The panel has been validated in multiple studies involving close to 15,000 men. We have also demonstrated that the panel is highly predictive of the long-term risk of distant metastasis in men followed for many years without screening. We propose to evaluate whether the clinical role of the panel could expand from decisions about diagnostic biopsy to those concerning immediate treatment decision-making and active surveillance protocols. We will first use data from five independent cohorts, three from Europe and two from the US, to determine whether the panel of four kallikrein markers can predict either unfavorable pathology at radical prostatectomy or post-treatment oncologic outcomes such as metastases. If so, the panel ? data from which may often be available from the diagnostic biopsy ? could be used to help decisions about treatment versus conservative management. Our second aim is to determine whether the panel of markers can predict the result of active surveillance biopsy. If so, using the panel to avoid biopsy in men at low risk of progression would decrease the number of biopsies required by active surveillance protocols, reducing morbidity and potentially increasing the acceptability of active surveillance as a management strategy. We also aim to determine whether the properties of the panel could be improved by either adding a novel marker, microseminoprotein-? (MSMB) or modifying measured marker levels in the light of marker-related single-nucleotide polymorphisms (SNPs.)